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1.
Cell Div ; 2: 11, 2007 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-17355622

RESUMEN

Ubiquitin is a highly versatile post-translational modification that controls virtually all types of cellular events. Over the past ten years we have learned that diverse forms of ubiquitin modifications and of ubiquitin binding modules co-exist in the cell, giving rise to complex networks of protein:protein interactions. A central problem that continues to puzzle ubiquitinologists is how cells translate this myriad of stimuli into highly specific responses. This is a classical signalling problem. Here, we draw parallels with the phosphorylation signalling pathway and we discuss the expanding repertoire of ubiquitin signals, signal tranducers and signalling-regulated E3 enzymes. We examine recent advances in the field, including a new mechanism of regulation of E3 ligases that relies on ubiquitination.

2.
Nat Cell Biol ; 8(11): 1246-54, 2006 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-17013377

RESUMEN

Many proteins contain ubiquitin-binding domains or motifs (UBDs), such as the UIM (ubiquitin-interacting motif) and are referred to as ubiquitin receptors. Ubiquitin receptors themselves are frequently monoubiquitinated by a process that requires the presence of a UBD and is referred to as coupled monoubiquitination. Using a UIM-containing protein, eps15, as a model, we show here that coupled monoubiquitination strictly depends on the ability of the UIM to bind to monoubiquitin (mUb). We found that the underlying molecular mechanism is based on interaction between the UIM and a ubiquitin ligase (E3), which has itself been modified by ubiquitination. Furthermore, we demonstrate that the in vivo ubiquitination of members of the Nedd4 family of E3 ligases correlates with their ability to monoubiquitinate eps15. Thus, our results clarify the mechanism of coupled monoubiquitination and identify the ubiquitination of E3 ligases as a critical determinant in this process.


Asunto(s)
Proteínas de Unión al Calcio/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Fosfoproteínas/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina/metabolismo , Proteínas Adaptadoras Transductoras de Señales , Sitios de Unión/genética , Proteínas de Unión al Calcio/genética , Catálisis , Complejos de Clasificación Endosomal Requeridos para el Transporte , Células HeLa , Humanos , Immunoblotting , Péptidos y Proteínas de Señalización Intracelular/genética , Modelos Biológicos , Mutación/genética , Ubiquitina-Proteína Ligasas Nedd4 , Fosfoproteínas/genética , Unión Proteica , Transfección , Ubiquitina-Proteína Ligasas/genética
3.
Proc Natl Acad Sci U S A ; 102(8): 2760-5, 2005 Feb 22.
Artículo en Inglés | MEDLINE | ID: mdl-15701692

RESUMEN

Plasma membrane receptors can be endocytosed through clathrin-dependent and clathrin-independent pathways. Here, we show that the epidermal growth factor (EGF) receptor (EGFR), when stimulated with low doses of EGF, is internalized almost exclusively through the clathrin pathway, and it is not ubiquitinated. At higher concentrations of ligand, however, a substantial fraction of the receptor is endocytosed through a clathrin-independent, lipid raft-dependent route, as the receptor becomes ubiquitinated. An ubiquitination-impaired EGFR mutant was internalized through the clathrin pathway, whereas an EGFR/ubiquitin chimera, that can signal solely through its ubiquitin (Ub) moiety, was internalized exclusively by the non-clathrin pathway. Non-clathrin internalization of ubiquitinated EGFR depends on its interaction with proteins harboring the Ub-interacting motif, as shown through the ablation of three Ub-interacting motif-containing proteins, eps15, eps15R, and epsin. Thus, eps15s and epsin perform an important function in coupling ubiquitinated cargo to clathrin-independent internalization.


Asunto(s)
Clatrina/fisiología , Endocitosis , Receptores ErbB/metabolismo , Ubiquitina/metabolismo , Proteínas Adaptadoras Transductoras de Señales , Animales , Células CHO , Proteínas de Unión al Calcio/fisiología , Cricetinae , Células HeLa , Humanos , Péptidos y Proteínas de Señalización Intracelular , Fosfoproteínas/fisiología
4.
J Bacteriol ; 186(21): 7353-63, 2004 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-15489447

RESUMEN

Transcription of the catabolic touABCDEF operon, encoding the toluene-o-xylene monooxygenase of Pseudomonas stutzeri OX1, is driven by the sigma(54)-dependent Ptou promoter, whose activity is controlled by the phenol-responsive NtrC-like activator TouR. In this paper we describe for the first time a peculiar characteristic of this system, namely, that Ptou transcription is activated in a growth phase-dependent manner in the absence of genuine effectors of the cognate TouR regulator. This phenomenon, which we named gratuitous activation, was observed in the native strain P. stutzeri OX1, as well as in a Pseudomonas putida PaW340 host harboring the reconstructed tou regulatory circuit. Regulator-promoter swapping experiments demonstrated that the presence of TouR is necessary and sufficient for imposing gratuitous activation on the Ptou promoter, as well as on other sigma(54)-dependent catabolic promoters, whereas the highly similar phenol-responsive activator DmpR is unable to activate the Ptou promoter in the absence of effectors. We show that this phenomenon is specifically triggered by carbon source exhaustion but not by nitrogen starvation. An updated model of the tou regulatory circuit is presented.


Asunto(s)
Proteínas de Unión al ADN/metabolismo , ARN Polimerasas Dirigidas por ADN/metabolismo , Regulación Bacteriana de la Expresión Génica , Oxigenasas/metabolismo , Regiones Promotoras Genéticas , Pseudomonas stutzeri/crecimiento & desarrollo , Factor sigma/metabolismo , Transactivadores/metabolismo , Carbono/metabolismo , Medios de Cultivo , Oxigenasas/genética , Pseudomonas stutzeri/genética , Pseudomonas stutzeri/metabolismo , ARN Polimerasa Sigma 54 , Tolueno/metabolismo , Transcripción Genética , Xilenos/metabolismo
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